PQBP1 – Renpenning Syndrome

This summary integrates extensive evidence linking PQBP1 (HGNC:9330) to Renpenning syndrome (MONDO:0010653), a well‐characterized X‑linked condition. A large number of unrelated probands (>30 [PMID:15782410]) and multiple family segregation studies ([PMID:31840929]) collectively support a strong gene‑disease association. Several independent studies have reported diverse pathogenic variants in PQBP1 including whole gene duplications, frameshift, and missense mutations that disrupt normal protein function.

The clinical genetic studies consistently document an X‑linked inheritance pattern, with affected males exhibiting core features such as intellectual disability, short stature, microcephaly, and decreased testicular size. Notably, a representative variant, c.559delT (p.Tyr187IlefsTer8), was identified in one cohort and is emblematic of the frameshift alleles impacting PQBP1 function ([PMID:30143497]). Additional segregation data from affected relatives further reinforces the disruption of PQBP1 in the disease pathogenesis.

Complementary functional assessments have revealed that PQBP1 plays a crucial role in pre‑mRNA splicing and transcription regulation. Several studies employing binding assays and cellular models have demonstrated that mutations – particularly within the WW domain – impair ligand binding and splicing efficiency, thereby contributing to the Renpenning syndrome phenotype ([PMID:20410308], [PMID:22710169]). These experimental results provide moderate but consistent support that the loss and/or alteration of PQBP1 function is central to disease mechanisms.

Some reports have noted atypical presentations, such as a female case with skewed X‑inactivation, which may influence the expressivity of clinical features. However, the preponderance of evidence in affected males and supportive experimental data minimizes conflicting interpretations and underlines a robust genotype–phenotype correlation.

Overall, the evidence from multiple case reports, family studies, and functional assays converges to confirm a strong association between PQBP1 variants and Renpenning syndrome. This association not only facilitates precise molecular diagnosis but also lays the groundwork for future therapeutic interventions targeting the underlying molecular pathology.

Key take‑home: PQBP1 is a critical gene in Renpenning syndrome, and its disruption should be considered in the differential diagnosis of patients presenting with intellectual disability and characteristic facial and growth abnormalities.

References

• American journal of medical genetics. Part A • 2011 • Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning PMID:21204222
• Annals of clinical and laboratory science • 2018 • First Korean Case of Renpenning Syndrome with Novel Mutation in PQBP1 Diagnosed by Targeted Exome Sequencing, and Literature Review PMID:30143497
• American journal of medical genetics. Part A • 2020 • Renpenning syndrome in a female PMID:31840929
• American journal of medical genetics. Part A • 2005 • Renpenning syndrome comes into focus PMID:15782410
• The Journal of biological chemistry • 2010 • Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing PMID:20410308

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